This Program Project represents a multi-disciplinary approach to investigating the pathophysiology of spinal cord injury (SCI), with the overall goal of developing therapeutic strategies directed at both the acute and chronic injury setting. Project 1 will investigate specific pathophysiology processes that may be targeted with acute neuroprotective strategies. Specifically, the effects of contusive SCI on apoptotic and necrotic cell injury will be assessed and therapeutic strategies, including neurotrophic factor and cytokine treatment, will be tested. The studies proposed in Project 2 will investigate novel immediate and delayed strategies to promote axonal tract regeneration and functional reinnervation of target neurons following SCI. The strategies include the combination of bridging permissive substrates (neurotrophin-engineered Schwann cells) with neuroprotective agents, neurotrophic factors, and unsheathing glia. In Project 3, the potential of utilizing CNS sem cell therapy for SCI will be studied. Pluripotent CNS stem cells whose fate can be precisely controlled in vitro will be transplanted into the injured cord to myelinate axons, to promote axonal regeneration, to reconstruct circuitry, to replace neurons, and restore function. Project 4 will make use of human spinal cord specimens to help identify cellular signals associated with subacute and chronic SCI histopathology. Specifically, this project will investigate which of the cellular and molecular responses observed in experimental animals are applicable to humans, and whether these responses are related to severity and outcome of CNS injury. The Program Project is supported by an established group of scientists who will provide the expertise necessary to conduct this multi-disciplinary program of SCI. Together, these experimental studies should enhance our understanding of the critical events associated with acute and chronic SCI and help to identify novel treatment strategies to promote neuroprotection, axonal regeneration, neuron replacement, myelination, and recovery of function in human SCI.